Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma

• ClinicalTrials.gov Identifier: NCT00808639
• Recruitment Status: Completed
• First Posted: December 16, 2008
• Results First Posted: May 15, 2014
• Last Update Posted: October 24, 2016
• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Beth Israel Deaconess Medical Center; Brigham and Women's Hospital; Amgen
• Information provided by (Responsible Party): Toni Choueiri, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: December 15, 2008
• First Posted Date: December 16, 2008
• Results First Submitted Date: January 14, 2014
• Results First Posted Date: May 15, 2014
• Last Update Posted Date: October 24, 2016
• Study Start Date: December 2008
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2014)

Number of Patients Achieving Pathologic Response [ Time Frame: After completion of 4 cycles of chemotherapy with pegfilgrastim support (cycle length 2 weeks) ]

Pathological response is defined as down-staging to </=pT1, N0 after chemotherapy with pegfilgrastim support.

• Original Primary Outcome Measures (submitted: December 15, 2008): To estimate the pathologic response of this patient population treated with neoadjuvant chemotherapy and pegfilgrastim followed by radical surgery with curative intent. [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: April 15, 2014)

• Number of Patients Experiencing Febrile Neutropenia [ Time Frame: After completion of 4 cycles of chemotherapy with pegfilgrastim support (cycle length 2 weeks) ]
  Febrile neutropenia defined per CTCAEv3 as Grade 3 or higher and treatment attribution possibly, probably or definitely-related.
• Number of Patients Experiencing Surgery-related Toxicity [ Time Frame: Surgery + 30 days ]
  Surgery-related toxicity defined per CTCAEv3 as Grade 2 or higher and treatment attribution possibly, probably or definitely-related.

Original Secondary Outcome Measures (submitted: December 15, 2008)

• To document the rate of febrile neutropenia and compare to historical standard for MVAC [ Time Frame: 3 years ]
• To document perioperative morbidity and mortality in this cohort. [ Time Frame: 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma
• Official Title: A Phase II Trial of Neoadjuvant Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma
• Brief Summary: The purpose of this research study is to test the effectiveness of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in combination with pegfilgrastim followed by radical surgery in patients with muscle-invasive urothelial carcinoma.

Detailed Description

• Participants will be given a study infusion schedule for each treatment cycle. Each treatment cycle lasts three weeks. The infusion of methotrexate will take place on the first day of each cycle. Infusions of vinblastine, doxorubicin and cisplatin will take place on the second day and an injection of pegfilgrastim will be given on the third day.
• During all treatment cycles participants will have a physical exam and will be asked questions about their general health and any problems they might be having and any medications they may be taking.
• Following completion of study treatment, but before surgery, participants will have an assessment of their tumor by CT scan of the chest and and MRI of the abdomen and pelvis.
• Following the participants surgery, we would like to keep track of their medical condition indefinitely, or until this study is officially completed. We would like to do this by calling the participants on the telephone once a year to see how they are doing.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Bladder Cancer
• Muscle-invasive Bladder Cancer

Intervention

• Drug: Methotrexate
  intravenously 30mg/m2 over 30 minutes
• Drug: Doxorubicin
  intravenously 30mg/ms over 15 minutes
• Drug: vinblastine
  intravenously 3mg/m2 over 30 minutes
• Drug: cisplatin
  intravenously 70mg/m2 in 1 liter NS with 12.5gm Mannitol over 2 hours after vinblastine completion
• Drug: Pegfilgrastim
  Given subcutaneously 24 hours after last chemotherapy dose

Study Arms

Experimental: Dose Dense MVAC

Chemo therapy with methotrexate, vinblastine, Adriamycin, Cisplatin

Interventions:

• Drug: Methotrexate
• Drug: Doxorubicin
• Drug: vinblastine
• Drug: cisplatin
• Drug: Pegfilgrastim

• Publications *: Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. doi: 10.1200/JCO.2013.52.4785. Epub 2014 May 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 15, 2008): 39
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: September 2016
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologic proof of urothelial cancer. Patients with all histologic subtypes are eligible as long as transitional cell carcinoma is predominant, with the exception of more than a few clusters of small cell carcinoma, which is treated with different chemotherapy and thus are ineligible
• Patients with primary tumors arising in the bladder or urethra are eligible if they have clinical T2-T4a disease
• Patients with primary tumors arising in the ureter or renal pelvis are eligible if they have either grade 3 tumors, or radiographic abnormality large enough to be recognized as an abnormal mass by CT/imaging
• Evaluation by a urologist and be deemed to be acceptable surgical candidates within 3 months of registration
• Adequate physiologic reserves as outlined in the protocol
• Clinical or pathologic N1 lymph node involvement (involvement of a single lymph node < 2cm in greatest dimension) are eligible. Patients with N2-3 or M1 disease are ineligible
• Determination of LV function with an EF > 50%
• Women of child-bearing potential must have a negative pregnancy test
• Patients of child-bearing or father-bearing potential must agree to use an acceptable form of birth control while on the study
• Patients with prior malignancy are eligible provided that the expected outcome from the prior cancer is such that this will not interfere in the delivery of this therapy, or the assessment of response in the cystectomy specimen
• 18 years of age or older

Exclusion Criteria:

• Current, recent (within 3 weeks), or planned participation with other experimental anti-cancer medications as part of clinical trials
• Prior treatment with doxorubicin
• Prior systemic cytoreductive chemotherapy for bladder cancer
• Blood pressure of > 160/100 mmHg. Patients whose blood pressure can be controlled with oral medication are eligible
• NYHA Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to study enrollment
• History of stroke or transient ischemic attack within 6 months prior to study enrollment
• Clinically significant peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Known history of central nervous system or brain metastases
• Major surgical procedure, significant traumatic injury within 21 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study
• Lactating women
• Patients who are not candidates for surgery, or unwilling to undergo surgery
• Patients with significant fluid collection
• Known hypersensitivity to any component of cisplatin, methotrexate, vinblastine, doxorubicin or pegfilgrastim

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00808639
• Other Study ID Numbers: 08-208
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Toni Choueiri, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Toni Choueiri, MD, Dana-Farber Cancer Instiutte
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current

Collaborators

• Beth Israel Deaconess Medical Center
• Brigham and Women's Hospital
• Amgen

Investigators

• Principal Investigator: Toni Choueiri, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: September 2016